Dosimetrically customizable brachytherapy carriers and methods thereof in the treatment of tumors

ABSTRACT

Brachytherapy radioisotope carrier systems and methodology for providing real-time customized brachytherapy treatment to subjects with tumors difficult to control using conventional radiation therapy techniques. The invention generally relates to devices, methods and kits for providing customized radionuclide treatments, to help cure, slow progression or regrowth, or ameliorate the symptoms associated with tumors.

PRIORITY CLAIM

This application is a continuation of U.S. patent application Ser. No.13/460,792, filed on Apr. 30, 2012, entitled “DOSIMETRICALLYCUSTOMIZABLE BRACHYTHERAPY CARRIERS AND METHODS THEREOF IN THE TREATMENTOF TUMORS”, which claims the benefit under 35 U.S.C. §119 of U.S.Provisional Patent Application Ser. No. 61/480,304, filed Apr. 28, 2011,and entitled “DOSIMETRICALLY CUSTOMIZABLE INTERSTITIAL RADIONUCLIDEBRAIN IMPLANTS, CARRIERS AND METHODS THEREOF”. The disclosures of theforegoing applications are hereby incorporated by reference in theirentirety.

FIELD

The invention generally relates to using radiation therapy to treattumors and more specifically to dosimetrically customizable carriers,kits and techniques for using the invention in the treatment of tumors.

BACKGROUND

Tumors in living organisms are highly variable in size, location andtheir amount of infiltration into normal tissues, the variability oftumors in general make them very difficult to treat with a one-size fitsall approach. Furthermore, the extent of tumors and/or void upondebulking are typically not known until presented in the operating room.Thus the options necessary to effectively treat a tumor or tumor bedneed to be quite diverse.

Tumors are difficult to eradicate surgically as their infiltrativenature often precludes microscopically complete resection without unduemorbidity or mortality. This local persistence of tumor cells may becontrolled if sufficient radiation can be delivered safely prior toregrowth and replication of the residual tumor cells. Debulking surgery,followed by radiation therapy in high doses, provides the best chancefor local control of a tumor. However, the ability to deliver high dosesof radiation in the post operative setting is frequently limited byintolerance of surrounding healthy tissue. Radiation therapy is dividedinto external beam radiation therapy (EBRT) or teletherapy and internalradiation therapy or brachytherapy (BT). The therapeutic index is therelative amount of healthy tissue receiving high doses of radiationcompared to the dose delivered to the tumor or tumor bed. Improving thetherapeutic index may increase local control of tumors and/or decreasethe morbidity of treatment. The inherently localized nature of BT isrecognized as a technique to improve the therapeutic index in tumortreatment with radiation.

Brachytherapy involves placing a radiation source either into orimmediately adjacent to a tumor. It provides an effective treatment oftumors of many body sites. Brachytherapy, as a component ofmultimodality cancer care, provides cost-effective treatment.Brachytherapy may be intracavitary, as in gynecologic malignancies;intraluminal, as in but not limited to esophageal or lung cancers;external surface, as in but not limited to cancers of the skin, orinterstitial, as in but not limited to the treatment of various centralnervous system tumors as well as extracranial tumors of the head andneck, lung, soft tissue, gynecologic sites, rectum, liver, prostate, andpenis.

The currently available brachytherapy devices and techniques are lackingin the following areas: 1) the current carriers are unable to easilyaccommodate anatomically conformal and reproducible brachytherapy doses;2) do not facilitate real-time dosimetric customization for sparingnormal tissue, while delivering effective and safe doses of radiation totumors; and 3) are not able to incorporate additional therapeuticagents, including chemotherapy, and viral, targeted, and DNA damagerepair inhibitors.

The present invention addresses the deficiencies associated with currentbrachytherapy devices for treating highly variable tumors and comprisesof novel brachytherapy radioisotope carrier systems and methodology forproviding real-time customized brachytherapy treatment to patients withtumors difficult to control using conventional radiation therapytechniques.

SUMMARY

The present invention generally relates to devices, methods and kits forproviding a customized radionuclide treatment in a patient to help cure,slow progression or regrowth, or ameliorate symptoms associated withtumors. And more specifically to a versatile dosimetrically customizablebrachytherapy system for providing a targeted radionuclide dose tospecific tissues on or within the human body.

An embodiment of the present invention comprises a radionuclide carriersystem comprising of one or more individual implantable carriersconfigured to hold radioactive seeds in a precise location relative to atreatment area in order to produce a dosimetrically customizable implantin real-time for an area to be treated and wherein the individualcarriers are small enough to fit in or on the area to be treated and thecarriers are selected from one or more tile carriers and/or gorecarriers. Additional carrier system embodiments may feature only one ormore tiles or one or more gores for delivering the radionuclide dose tothe tissue of interest.

An additional embodiment of a radionuclide carrier system is thecustomization and use of a preplanned dosimetry based on precisedimensions and properties of the carriers to optimize the therapeuticindex for an affected area. With additional embodiments includingprecise dimensions and properties of the carriers by utilizinggelatin-based or collaged-based biocompatible materials of differingthicknesses below and/or above a radiation source to act as a spacer toachieve a desired radiation dose delivery and a sparing of normaltissue.

Another additional embodiment achieves the preplanned proper dosimetryby including a layer of tantalum, tungsten, titanium, gold, silver, oralloys of these or other high Z materials as a foil, grid or strip,internal to or on a surface of the carrier to facilitate sparing ofnormal tissue by diminishing the penetration of the radiation intoadjacent normal tissues.

Additional embodiments include carriers manufactured as prefabricatedcarriers of various shapes and sizes; and some carriers may be preloaded“hot” with the radioactive seeds or “cold” in order to allow theradioactive seeds to be loaded with specifically desired seeds justprior to an implant procedure.

Further embodiments contemplate carriers which may be configured for theuse of one or more low-energy radioactive seeds selected from Cs 131, Ir192, I 125, Pd 103 or other isotopes used intra-operatively followingsurgical resection to form a permanent implant.

Yet further embodiments may include carriers with short rangeradioisotopes emitting beta or alpha particles.

Another embodiment of a carrier system comprises carrying additionaltherapeutic modalities including chemotherapeutic agents, viraltreatments, targeted therapies, and/or DNA damage repair inhibitors.

Additional contemplated features of the carriers may includedifferential color coding to mark end seeds with higher radiationstrengths than middle seeds for improved radiation dose distribution foruse with limited size and irregularly shaped tumors/tumor beds; arrows,color-coded dots or other visual markers to indicate a properorientation of carriers in relation to the seeds and treatment areas;indicator lines to allow a user to trim or shape a carrier as neededwhile maintaining the desired spacing for the calculated dosimetry; andvisual and tactile indicators for a user to differentiate the tops frombottoms of carriers in the operating room/operative field and tomaintain correct orientation and desired dosimetry.

A further additional embodiment for the carrier system comprises aprogram/spreadsheet/nomogram to guide a user in the planning of implantsand to assist in ordering seeds/carriers based on preoperative shape,lesion size, location, histology and number of seeds needed. Anotherembodiment comprises a carrier system that is visible on CT andfluoroscopy, and/or is MRI compatible to allow the user to make accurateintra- and post-operative assessments.

An additional embodied radionuclide carrier system is contemplatedhaving at least two individual implantable carriers comprising; at leastone tile carrier and one gore carrier; and each carrier is configured tohold radioactive seeds in a precise location relative to a treatmentarea to produce a dosimetrically customizable implant in real-time foran area to be treated and the individual carriers are small enough tofit in or on the area to be treated. The at least one tile carrierincluded in the embodied radionuclide carrier system comprisesbiocompatible materials of differing thicknesses below and/or above aradiation source(s) in order to act as a spacer as well as the use of alayer of tantalum, tungsten, titanium, gold, silver, or alloys of theseor other high Z materials as a foil, grid or strip internal to or on thesurface of the carrier to facilitate sparing of normal tissue bydiminishing the penetration of the radiation into adjacent normaltissues. The at least one gore carrier included in the embodiedradionuclide carrier system also comprises biocompatible materials ofdiffering thicknesses below and/or above a radiation source to act as aspacer to achieve a desired radiation dose delivery and sparing ofnormal tissue. The radionuclide carrier system of the present embodimentis used for intraoperative permanent brachytherapy in treatment oftumors within the central nervous system or its cavities or coverings;and comprises a conformable but dosimetrically stable design fordelivery and positioning of radioactive seeds to produce a customizableimplant in real-time, piece by piece, for each patient and tumor.

Yet further embodiments of the present invention include inserting theindividual implantable radionuclide carriers into or onto a tumor, avoid remaining following a tumor resection, or a tumor bed; to helpcure, slow progression or regrowth, or ameliorate symptoms associatedwith the tumor.

Additional embodiments of the radionuclide carrier system is forintraoperative permanent brachytherapy in treatment of various tumors ofthe body, including but not limited to tumors of the central nervoussystem, head and neck, soft tissues, bone, spine, lung, breast, skin,esophagus, stomach, liver, intestines, colon, rectum, prostate,pancreas, retroperitoneal space, kidney, bladder, pelvis, ovary, cervix,fallopian tubes, uterus and vagina.

BRIEF DESCRIPTION OF THE DRAWINGS

The principles of the present invention will be apparent with referenceto the following drawings, in which like reference numerals denote likecomponents:

FIG. 1 shows a perspective view of an embodied carrier device in a tileform.

FIG. 2 shows a front plan view of another embodied carrier device in atile form.

FIG. 3. Comprises a perspective view of another embodied carrier devicein tile form wherein the tile further includes a metal foil at theantipodal surface distal to the treatment zone.

FIG. 4 comprises FIGS. 4A and 4B which show two perspective views ofalternative shape designs for tile carriers.

FIG. 5 represents a drawing in which embodied individual tiles are shownin use in a post-operative cavity after tumor debulking.

FIG. 6 shows a perspective view of another contemplated carrier systemin tile form.

FIG. 7 comprises FIGS. 7A, 7B, and 7C which are front plan views ofthree embodied carrier systems in gore form and in a 2-dimensional form.

FIG. 8 comprises FIGS. 8A and 8B which are front plan views of the gorecarrier shown from 7B when in 3-dimensional forms.

FIG. 9 comprises FIGS. 9A and 9B which are perspective views of moreembodied gore carriers in different shapes.

FIG. 10 comprises FIGS. 10A and 10B which represents two views of anembodied carrier in gore form.

FIG. 11 shows a perspective view of another embodied carrier in goreform.

FIG. 12 comprises FIGS. 12A and 12B wherein FIG. 12A shows an embodiedneedle radionuclide seed loading device contemplated and FIG. 12B showsa perspective view of a carrier device with proper radionuclide seedplacement.

FIG. 13 comprises FIGS. 13A, 13B and FIG. 13C wherein FIG. 13A shows aperspective view of a lid to an embodied loading device; FIG. 13B showsa perspective view of the base of an embodied loading device; and FIG.13C shows a perspective view of and an embodied loading device with thelid in its secured position on the base.

FIG. 14 is a perspective view of an embodied carrier in tile form placedin a loading device for enhanced radionuclide loading capabilities.

FIG. 15 is a top plan view of an embodied carrier in gore form placed ina loading device for enhanced radionuclide loading capabilities.

FIG. 16 illustrates exemplary preoperative shapes and locations andtumors to be treated with one or more of the embodied devices of thepresent invention.

FIG. 17 illustrates exemplary the shape and location of variouspost-operative cavities to be treated with one or more of the embodieddevices of the present invention.

FIG. 18 comprises FIGS. 18A, 18B, 18C, 18D and 18E each show differentapplications and configurations of the carrier systems for treatingvariable target treatment areas.

DETAILED DESCRIPTION Definitions

For the purposes of the present invention Brachytherapy is defined asradiation treatment in which the source of the radiation is placed closeto the surface of the body or within the body or a body cavity a shortdistance from the area being treated.

For the purposes of the present invention Teletherapy is defined asradiation treatment in which the source of the radiation is at adistance from the body.

For the purposes of the present invention High Dose Rate is consideredto be defined as the treatment with radiation doses above 12,000 cGy/hr.

For the purposes of the present invention Low Dose Rate is considered tobe defined as the treatment with radiation in the dose range of 400-2000cGy/hr

For the purposes of the present invention High Z Materials areconsidered to be defined as any element with an atomic number greaterthan 20, or an alloy containing such materials.

For the purposes of the present invention the term Hot is considered tobe a material that is Radioactive and the term Cold is considered tomean a material is low in radioactivity; or not radioactive.

For the purposes of the present invention Dosimetry is defined as theprocess of measurement and quantitative description of the radiationabsorbed dose (rad) in a tissue or organ.

For the purposes of the present invention a Tile Carrier sometimes alsoreferred to as a GammaTile is defined as a type of radionuclide carrierthat is planar and maintains a two-dimensional planar geometry whenplaced in use to treat tumors.

For the purposes of the present invention a Gore Carrier sometimes alsoreferred to as a GammaGore is defined as a type of radionuclide carrierthat, while initially planar, will assume a 3-dimensional shape whenarranged and placed into an operative cavity or similar space andconform to the treatment environment while maintaining the geometrynecessary for an effective implant.

For the purposes of the present invention the term Interstitial isdefined as pertaining to parts or interspaces of a tissue.

For the purposes of the present invention the term Tumor: is defined asan abnormal growth of tissue resulting from uncontrolled, progressivemultiplication of cells; which can be benign or malignant.

For the purposes of the present invention the term Malignant is definedas tumors having the potential for or exhibiting the properties ofanaplasia, invasiveness, and metastasis.

For the purposes of the present invention the term Cancer is defined asany malignant, cellular tumor.

For the purposes of the present invention the term Chemotherapy isdefined as a cancer treatment method that uses chemical agents toinhibit or kill cancer cells.

Application of Embodied Carriers in Central Nervous System Tumors

Despite meticulous surgical technique, tumors metastatic to the brain orspine often recur at or near the site of resection. This is because itis rarely feasible to resect these tumors with pathologically negativemargins, especially in the more eloquent regions or where lesions areadjacent to vascular structures or nerves. Radiation therapy, utilizingan increasingly large variety of techniques, has been shown to be thesingle most effective adjuvant treatment to help prevent recurrence ofmalignant brain tumors. Interstitial brachytherapy combined withsurgical resection of central nervous system tumors has been in use forseveral decades. Various types of radioactive sources are inserted underdirect visualization during the surgery, as potentially more costeffective and less time-consuming therapy, without compromisingoutcomes.

Nevertheless, techniques for interstitial brachytherapy (BT) of centralnervous system tumors have remained relatively crude. The brachytherapydevice and methods embodied in the present invention improve thedelivery of radiation by creating a carrier system to createcombinations of carriers (tiles and/or gores) each with radioactivesources contained within. These carriers, known as tile carriers or“GammaTiles” (GT's) and gore carriers or “GammaGores” (GG's) can bepositioned to fit into operative beds by customizing them to the shapeand size of individual operative cavities. The GTs can be tailored toprotect sensitive normal structures, such as nerves or normal brain,while delivering desired high doses of radiation to the preciselocations at highest risk of recurrence. The GTs may also be used ascarriers for short-range radioisotopes emitting beta or alpha particlesor for delivery of other therapeutic modalities, includingchemotherapeutic agents, viral treatments, targeted therapies, and/orDNA damage repair inhibitors. They may also be designed to contain highZ materials and/or biocompatible spacers to afford significantdirectionality to the radiation treatment.

Application of Embodied Carriers Outside the Central Nervous System

Brachytherapy has been used to treat many tumors of extracranial sitessuch as head and neck, lung, soft tissue, gynecologic, rectum, prostate,penis, esophagus, pancreas and skin. Brachytherapy (BT) can be usedalone or in combination with external beam radiotherapy and/or surgery.Patient outcomes are critically dependent upon proper patient selectionand implantation technique. In general, patients with tumors that areintimately associated with critical normal structures to be preservedsuch as nerves, vessels, cosmetically apparent areas or visceral organscannot be completely resected without undue morbidity or mortality.These tumors may be good candidates for BT performed in conjunction withsurgical resection. Currently available techniques to produce thereliable source spacing needed for optimal geometry and subsequentlyradiation dosimetry, require catheters and shielding that are relativelybulky and therefore poorly conforming to the treated area. Consequently,they require considerable capital investment and the presence of a teamof experts for effective use; and when preformed intraoperatively mustbe undertaken in a specially shielded operating room to avoidirradiation of adjacent staff and patients. These shortcomings limit theavailability of these therapies to very few centers and compromiseoutcomes by decreasing tumor control and increasing complications fromtherapy. The brachytherapy device and methods contemplated in thepresent invention facilitates achieving optimal radioactive sourcearrangements for permanent low dose rate (LDR) BT in a user-friendly,readily available and cost-effective manner, by using a carrier systemof geometrically customizable carriers (GTs/GGs) to contain radioactivesources to be placed into tumors or tumor beds.

Furthermore, the embodiments of the present invention also enables usersto preferentially spare sensitive normal tissue without compromising theability to deliver high dose radiation customized to both tumor andpatient anatomy.

Additional embodiments of the tile and or gore carriers may include theability of the tile and or gore carriers to deliver other cytotoxicagents, such as chemotherapy drugs or very short range radioactivesources such as Y-90 and alpha particles for placement directly intotumors, while maximally sparing normal tissue.

Illustrative embodiments of the invention are described below. In theinterest of brevity, not all features of an actual implementation aredescribed in this specification. It will, of course, be appreciated thatin the development of any such actual embodiment, numerousimplementation-specific decisions such as compliance with regulatory,system-related, and business-related constraints, which will vary fromone implementation to another, must be made to achieve the specificgoals. Moreover, such a developmental effort might be complex andtime-consuming but with the benefit of this disclosure, would be aroutine undertaking for those skilled in the art of radiation therapy.

Carrier Systems

Generally the carrier systems described herein and exemplified in FIGS.1-11 involve the utilization of small individual implantable carriers inthe form of tiles (as shown in FIGS. 1-6) and gores (as shown in FIGS.7-11) designed to be bearers of therapeutic agents such as radioactiveseeds to produce a dosimetrically customizable implant in real time foreach patient and lesion.

The carrier systems are designed to: create a carrier which allows formore precise and predictable dosimetry; an improved geometry with abetter orientation of seeds to one another especially in the settings ofreal-time, intraoperative environments; is fully customizable to adjustto size/volume, location, and tumor type; and can provide differentialdosing of tumor/tumor bed vs. normal tissues.

The carrier systems embodied are generally made of biocompatiblematerials known in the art and more specifically may be made of gelatinbased or collagen based biocompatible materials.

Example 1 Tile Carrier Embodiment

FIGS. 1-6 show various exemplifications of carrier devices in tile formembodied in the present invention.

FIG. 1 shows a perspective view of an embodied carrier device 100 in atile form wherein the tile 101 serves as a loadable shieldable spacerfor a radioactive seed 199 and wherein the embodied tile 101 comprises apre-formed loading channel 150 which runs from a proximal end 103through to a distal end 105. Additionally there is an antipodal surface110 opposite of the treatment surface 120. The approximate dimensionscontemplated of a tile as shown here would be a square with each sideabout 1 cm and the depth of the device as measured as the distance fromthe antipodal surface 110 to the treatment surface 120 may be about 2-7mm, with 3-6 mm preferred, 4-5 mm more preferred, and 4 mm mostpreferred. A loading channel 150 may be preformed as shown or created attime of radioactive seed 199 placement. The seed 199 will generally beplaced in the center of the loading channel 150 and there are variousways to insure proper placement of the seed 199 within the channel.Furthermore the antipodal surface 110 may additionally comprise variouscolored markers, indicators and textural features which may furtherinsure proper orientation of the tiles 101 when being placed.

FIG. 2 shows a proximal 203 or end view of another embodied tile formcarrier 201 and demonstrates the positioning of the loading channel 250in respect to the tile 201. In this example the loading channel 250itself may be offset within the tile 201 such that the channel 250 islocated closer to either the antipodal 210 or the treatment 220 surfacedepending on the exposure wanted and or the shielding constraintsdesired with the radionuclide seed 199 (not shown) within the loadingchannel 250. In the case shown there is a thin layer of material 230 onthe antipodal side 210 and a thicker layer 240 in which the loadingchannel 250 is formed.

FIG. 3 shows a perspective view of another embodied tile 301 wherein thetile further includes a metal foil 311 on the antipodal surface 310. Oneor more surfaces can include a metal foil layer 311 on the antipodalsurface 310 such as gold to block rads from escaping and/or redirectthem or focus them towards the target treatment area. Some of the metalscontemplated for use include a layer of tantalum, tungsten, titanium,gold, silver, or alloys of these or other high Z materials on theantipodal aspect (additionally the metal layers may be locatedinternally between spacing layers in either GammaTile or GammaGores notpresently shown) to provide sparing of normal tissue in portions ofbrain and elsewhere where there is very limited physical space.Additionally, the embodied tile 301 may include a loading channel 350which may be located between an upper spacer layer 330 which may be thethicker portion located away from the treatment surface 320 and a lowerspacer 340 which is the thinner portion located adjacent to thetreatment surface 320.

The present invention contemplates of carrier construction usingdifferential thicknesses of biocompatible materials below and/or abovethe radiation sources (as shown in FIG. 3 above) to achieve differentialradiation dose delivery with relative sparing of normal tissue alongwith the use of a layer of tantalum, tungsten, titanium, gold, silver,or alloys of these or other high Z materials on the antipodal aspect(side away from the tumor) or internal to the Tiles or Gores to providesparing of normal tissue in portions of the body such as the brain, andanywhere there is very limited physical space.

FIG. 4 shows a perspective view of two alternative tile shapes includinga circular tile 401 and a square tile 501 in any given tile contemplatedin the present invention the loading channel 450, 550 may be preformedor may be marked for loading with a sharp instrument such as a needle,or may be blank and the channel may be formed wherever the userdetermines makes the most sense from a dosimetry, geometry and ororientation standpoint.

FIG. 5 represents a drawing in which embodied individual tiles 501 areshown in use in a post-operative cavity after tumor debulking. In thiscase four individual or interconnected tiles 501 are placed within thecavity adjacent to the tissue margins where the debulking occurredwherein the radionuclide seeds 599 target the tissue around the lesionmargin and the tile 501 shields the other tissues and void space fromthe radionuclide exposure. The treatment surface 520 lies closest to thetumor bed and the antipodal surface 510 faces the void space. Furtherembodiments contemplated but not shown include the use of notches,matched tongue and groove, slot/groove, key lock, logo-block or similarmating/matching type systems to secure and it the tiles 501 next to eachother to provide optimal geometry and orientation and increase thecustomization to a broad realm of effective treatment possibilities.

FIG. 6 shows a perspective view of another contemplated carrier system600 in tile 601 form. The tile sheet shown 601 includes three equal sizetiles. The carrier system 600 is marked with indicator lines 659, whichwould allow users to trim/shape tiles 601 to the needed size but stillmaintain desired spacing for the dosimetry. The use of tiles 601 ofcertain precise dimensions allow for the carrier to guide the user tomaintain the precise and preplanned dosimetry needed to produceeffective and safe outcomes. For example a contemplated device may be1.0 cm on center spacing between seeds in tile, and 0.5 cm spacing totile edge. So the next tile, if added, maintains overall 1.0 cm spacingpattern and the preprinted “cut here” lines 659 shown may be 0.5 cmbetween each seed so a 2×3 linear carrier could be size-trimmed to a 2×2tile or 2×1 tile in the operating room. Additionally, the antipodalsurface 610 of FIG. 6 includes a top differentiator with the markings659 and 657 provided. In this case there are trim lines loading channelorientation lines 655, seed location markings 657 and trim lines 659.Additional concepts for differentiating the tops (antipodal surface 610)from bottoms (treatment surface 620) of the carriers in the operatingroom/operative field; can utilize color, texture, glossy/dull, etc, tomaintain correct orientation, and therefore, optimal dosimetery.Additionally, both ends 603 and 605 of the tile or just the proximal end603 may be marked with loading channel placement guides 651 for tiles601 fully customizable and not including a preformed loading channel 650(not present in this tile).

The present carriers may include the use of differential color codes tomark end seeds with higher radiation strength than the middle seeds forimproved radiation dose distribution for use with limited size andirregular shape targets.

Additional carriers may include the use of markers (color coded dots,arrows, etc) to indicate proper orientation of the tiles. For example,as seeds have both a long and short axis that may not be readilyapparent once in the tile, and tiles may be square, or adjacent to othertiles, “green arrow to green arrow, red arrow to red arrow” couldindicate both correct seed orientation, and give another guide toprecise line-up during placement.

The carriers may be manufactured in multiple size and shapeprefabricated tiles of various shapes and sizes (e.g., 1×1 cm, 2×2 cm,1×3 cm, 2×3 cm, 1×4 cm); these may be preloaded (hot) with theradioactive seeds, or cold to allow for the radioactive seeds to beplaced within the tumor or bed just prior to the procedure, whichsimplifies manufacture of tile for greater variety of carriers, reducesthe waste of unused “hot” carriers, and reduces the radiation exposureof the staff.

Additional carriers may also have an impermeable membrane, bio-compound,high Z material or other barrier, which acts to prevent or impede themigration of the compound(s) or agents from the side(s) of thecarrier(s) adjacent to the resected tumor to the antipodal side(s) ofthe carrier(s)(adjacent to normal tissue) and vice versa to create adifferential therapeutic impact on the operative bed vs. adjacenttissues.

Additional carriers may use differential thickness of tissue equivalentmaterial below and/or above the tiles and/or a construction of differinghigh z materials (or just the seed “tube” built into the tile) toachieve the desired radiation dose delivery or normal tissue sparingtargeting.

Example 2 Gore Style Carriers

FIGS. 7-11 show various exemplifications of carrier devices in gore formembodied in the present invention.

One problem associated surgeons and oncologists often face when treatinga subject include a subject with spherical and semisphericalintracranial lesions which are common and thus so are similarly shapedpostoperative cavities. Any useful carrier and coverage will need toadapt to this shape while being able to be implanted into the brain, andstill maintain “ideal” or nearly ideal geometry. One solution embodiedby the present invention includes the creation of two-dimensional goresthat act as carriers, and when loaded with seeds and placed in thecavity conform to the three-dimensional environment while maintaininggeometry of implant. In addition to the three-dimensional nature of thecarrier, the carrier may possess additional possible propertiespreviously mentioned including spacing function, differential thickness,and the possibility of combining with high-z materials for radiationprotection. These carriers may also be designed so as to be compatiblewith placement of adjacent tiles or gammatiles as needed for additionalintraoperative flexibility.

Additionally the gore-type carrier may be pre-manufactured in specificdimensions and available in a variety of sizes and/or capable of beingtrimmed to make smaller or combined to make bigger at time of use. Thedimensions decided upon can be customized by the user based upon thetumor/cavity size and characteristics to achieve the necessary geometry.

Although certain design shapes are shown as exemplary products in FIGS.7-11, other geometric shapes such as regular or irregular polyhedronsalso may be used as gore-style carriers.

FIG. 7 comprises FIGS. 7A, 7B, and 7C which are front plan views ofthree embodied carrier systems in gore form and in a 2-dimensional form.The general gore designs include petals, flaps, and/or a combination ofpetals and flaps. FIG. 7A shows a 2 dimensional gore design 701 withcomprising petals 744 and flaps 746. FIG. 7B shows a gore 801 withpetals 844 and flap 846 but in the design the flaps have an extendedlength to provide for a different geometrical or size application. FIG.7C shows a gore 901 with a Bi-concave design with double petals 944.

FIG. 8 shows FIGS. 8A and 8B which are front plan views of the gorecarrier 801 shown 7B when in 3-dimensional forms. FIG. 8A shows the gore801 rolled up to cover a 3-dimensional space which in more cylindricaland FIG. 8B shows the gore 801 rolled up with the petals 844 foldedinward which creates a closed cylinder with a rounded top 3-dimensionalconformation.

The proportions are generally fixed by height, width and length, and setby need to maintain ideal implant geometry of seed spacing. The exactlength and width depends upon the cavity size but the gore carrieritself may be pre made and/or pre-sized. The gore-type carrieradditionally may have seed location presets.

FIG. 9 includes FIG. 9A which shows a 2-dimensional gore designs 1001,with petals 1044, and flaps 1046. The antipodal surface 1010 is viewableand the treatment surface 1020 is hidden. The gore 1001 further includesmarking identifiers on the antipodal surface 1010 including loadingchannel orientation lines 1055 and seed location markings 1057.Additionally, both ends 1003 and 1005 of the gore or just the proximalend 1003 may be marked with loading channel placement guides 1051. FIG.9B shows a gore 1101 with petals 1144 and flap 1146 but in this designthe flaps have an extended length to provide for a different geometricalor size application. For example, the extended length flaps may providea better fit in a larger cavity. In both FIGS. 9A and 9B the gore isrolled inward and the antipodal sides 1010 and 1110 respectively are notviewable once the gore is placed in its rolled up 3-dimensionalconfiguration.

FIGS. 10A and 10B show another embodied gore 1201 wherein FIG. 10A showsa perspective view with the antipodal surface 1210 viewable and FIG. 10Bis a plan view of the treatment surface 1220 which shows the seed 1299distribution within the gore 1201. The gore is designed to roll up andthe treatment surface 1220 faces the tumor or treatment bed and theantipodal surface 1210 faces the interior of the 3-dimensionalsphere-like gore. This bi-concave design with double petals, may best beused in more spherical type cavities.

FIG. 11 shows a perspective view of another embodied carrier in gore1301 form wherein the treatment surface 1320 includes an additionallayer 1313 which may be used to provide for a localized delivery ofradioactive materials such as gamma or beta irradiation or alphaparticles along with chemotherapy agents ortumoricidal/targeted/immunotherapeutic or viral/viral vector agent(s) onthe side(s) of the carrier(s) adjacent to the tumor.

The carriers of the present invention may also provide for the use of asmall implantable individual carrier constructed for the localizeddelivery of radioactive materials such as gamma or beta irradiation oralpha particles along with radiation sensitizing agents and/or radiationdamage repair inhibitors on the side(s) of the carrier(s) adjacent tothe tumor.

The carriers of the present invention may also provide for the use of asmall implantable individual carrier constructed for the localizeddelivery of radioactive materials such as gamma or beta irradiation oralpha particles with or without other radiation protection compounds onthe side(s) of the carrier(s) antipodal to the radiation source and/ortissue growth promotion/healing factor compounds on the side(s) of thecarrier(s) antipodal to the radiation source.

The general gore designs include petals, flaps, and/or a combination ofpetals and flaps. The proportions are generally fixed by height, widthand length, and set by need to maintain ideal implant geometry of seedspacing. The exact length and width depends upon the cavity size but thegore carrier itself may be pre made and/or pre-sized. The gore-typecarrier additionally may have seed location presets. When the gore-typematerial is similar to the petal flap system found in FIG. 9A the petalsand flaps offset to maintain seed spacing. The seed spacing contemplatedmay range from 0.5 cm to 1.5 cm, with 0.75 cm to 1.25 cm preferred, 0.8cm to 1.2 cm more preferred and 1.0 cm a most preferred seed spacinginterval between seeds.

The present invention also may include the use of a small implantableindividual carrier constructed for the localized delivery of radioactivematerials such as gamma or beta irradiation or alpha particles alongwith chemotherapy agents or tumoricidal/targeted/immunotherapeutic orviral/viral vector agent(s) on the side(s) of the carrier(s) adjacent tothe tumor.

The present invention also may include the use of a small implantableindividual carrier constructed for the localized delivery of radioactivematerials such as gamma or beta irradiation or alpha particles alongwith radiation sensitizing agents and/or radiation damage repairinhibitors on the side(s) of the carrier(s) adjacent to the tumor.

The present invention also may include the use of a small implantableindividual carrier constructed for the localized delivery of radioactivematerials such as gamma or beta irradiation or alpha particles alongwith radiation protection compounds on the side(s) of the carrier(s)antipodal to the radiation source and/or tissue growth promotion/healingfactor compounds on the side(s) of the carrier(s) antipodal to theradiation source.

The tiles and or gores in the present invention include the adaptabilityof the carrier system to be isotope specific and manage the radionuclidestrength and exposure to users and normal (non-targeted) tissues with avariety of measures including differential thicknesses as shown above,seed-tubes (not shown), shielding materials, or spacing facilitators toplace radiolabeled seeds in best place in regards to treatment of targetand non-treatment of non-target.

The carriers may be MRI compatible and/or visible on fluoroscopy and CTto facilitate accurate intra- and post-operative assessment.

The small individual implantable tiles and/or gores are designed to becarriers for radioactive seeds used to produce a dosimetricallycustomizable implant in real time for each patient and tumor.

Radionuclide Seed Loading

FIG. 12A demonstrates the use of a loading needle apparatus 2000contemplated in the present invention. The apparatus 2000 comprises aneedle 2010 attached to a specific vicryl thread 2020 and at least oneradionuclide seed 2099 in a strand depending on the carrier andconditions to be loaded. The vicryl thread 2020 comprises a regularcolor section of thread 2025 and an offset color portion of thread 2030.When the offset color portion of thread 2030 is visible out of eitherend of a gore carrier, tile carrier or carrier loader the visualpresence is indicative that the seed is not placed in its properlocation. FIG. 12B exemplifies the use of a needle apparatus 2000, theneedle apparatus is used to penetrate the tile carrier 2001 and create aloading channel 2050 through the tile 2001. When the seed is placed atthe proper depth all of the offset color 2030 (such as purple) vicryldisappears inside of the tile device and the regular color thread 2025is trimmed away.

The present invention may use a variation of seeds in any carrier inorder to provide the best dosimetry for the patient tumor and space.Additionally, the loading strands may include one or more of the sameseeds or various combinations of well-known low energy radioactive seedssuch as Cs 131, Ir 192, I 125, Pd 103 or others commonly known in theart. The seeds placed within the carriers are generally placed as atherapeutic agent in the form of permanent implants intra-operativelyfollowing surgical resection, but there may be instance where implantsare interchanged removed or replaced.

In other possible loading carriers (Not shown) the carrier may includean “up” or “top” designation on the side opposite of the target zonesurface. The hot seed may be encased in a plastic cartridge and loadedinto the device with a colored vicryl or similar thread, such that whenthe seed is loaded into the appropriate position within the tile onlycertain thread colors are visible, once the alignment is complete thestrings on both sides may be pulled, thus pulling the two halves of theplastic cartridge shielding the hot seed. And thus allowing theunshielded hot seed to reside in its proper position within the tiledevice.

Loading Devices

The present invention also includes a specialized loading devicedesigned to enable the medical team to create a carrier for each patientand tumor reliably, reproducibly and efficiently.

FIGS. 13-15 demonstrate the use of a specialized loader system forloading the carriers of the present invention with radioactive seeds.The loaders of the present invention may be used with the carrierseither to create prepackaged hot carriers or to load “cold” carriersjust prior to use.

The embodied loaders can be single or multi-use, sterilizable, andshielded if desired. They are designed to load either standard or high-Zmaterial carriers in an accurate, efficient, and real-time manner. Theloaders are of similar designs, dimensionally specific, and eachconsists of two components, the base and the lid.

The base of the loaders functions to: 1) guide the initial path of theloading needle for seed placement in the carrier; 2) provide dimensionalstability to the soft carrier during the loading process; 3) center thecarrier left-right within the base during the loading process; and 4)shield the user.

The lid of a contemplated loader function to: 1) guide the final path ofthe loading needle, entirely through the carrier; 2) provide dimensionalstability to the soft carrier during the loading process; 3) positionthe carrier superior-inferiorly within the base during the loadingprocess; 4) position the carrier front to back within the base duringthe loading process; and 5) shield the user.

The loader designs of the present invention can be made to accommodate awide variety of GammaTile and GammaGore dimensions and styles. They areillustrated to accommodate seed-in-suture, but can be easily adapted forloose seeds or other configurations.

When loading a seed in suture a needle longer than the loader is usedand pulled through the loader channel holes on the proximal end of thebase and the distal of the lid. Once the needle protrudes it is pulledthe rest of the way with clamps or a needle-nose plier. For example, ifthe user uses a 60 mm loader the user would want to use a 70 mm needleto feed through the loader channels and deposit the seeds within thecarrier.

FIG. 13 includes FIGS. 13A and 13B wherein FIG. 13A shows a perspectiveview of a lid 3020 to an embodied loading device 3000. FIG. 13B shows aperspective view of the base 3010 of an embodied loading device 3000.And FIG. 13C shows a perspective view of an embodied loading device 3000with the lid 3020 in its secured position on the base 3010. The lid 3020has a bottom surface 3007 and a top surface 3009, a proximal end 3023and a distal end 3025, and a loading bed insert 3071 located on thebottom surface 3007 and running from the proximal end 3023 to the distalend 3025. Additionally there are loading channel 3053 exit holes (notshown) extending through the distal end 3025 of the lid. The base 3010as shown in FIG. 13B comprises of the proximal end 3013 and a distal end3015, a proximal end loading channel 3051 and a loading channel supportstructure 3055, which provides enough depth to guide a needle in aconsistent and accurate pathway as the needle tip travels through anyloading material if present, and exits out a loading channel exit hole3053. Additionally the loader 3000 comprises a loading bed 3070 in whichappropriately sized carrier material is placed to be loaded. Once acarrier is placed into the loading bed 3070 to be loaded, the lid 3020is placed onto the base 3010 such that the loading bed insert 3071located on the bottom surface 3007 of the lid 3020 engages with theloading bed 3070 portion of the base 3010. The depth of the loading bedinsert 3071 is chosen so that it is deep enough to sandwich and thecarrier material in place during the process of loading, but not to muchdepth which crushes the carrier, and repulses the ability of the loadingneedle to extend through a loading channel 3050.

FIG. 14 is a perspective view of the embodied tile carrier 601previously shown in FIG. 6 when placed in the loading bed 3070 of theloading device 3000 of FIG. 13. FIG. 14 shows the tile 601 is placedwithin the loading bed 3070 portion of the loader 3000. The lid 3020portion of the loader has been removed so that the tile 601 is visibleand one can see that the orientation lines 655 of the tile 601 aligndirectly with the proximal end loading channel 3051 such that when aneedle loader enters through the proximal end loading channel 3051 andextends through the loading channel support structure 3055 and entersinto the loading bed portion 3070 of the base 3010 where a carrier tile601 is in a secured position; the loading needle enters into thepredetermined placement on the tile 601 based on dosimetry needs fortreatment. And if the lid 3020 were present, the needle would extendthrough the loading channel exit hole 3053 and exit out of the deviceleaving the loaded carrier 601 behind.

When the needle loading apparatus is one such as that described in FIG.12A, the needle apparatus 2000 feeds through the proximal end loadingchannel 3051 and extends through the loading channel support structure3055 and enters into the loading bed portion 3070 of the base 3010 wherecarrier tile 601 is in its secured position. The needle apparatus 2000feeds through the tile carrier 601 and exits out the loading channelexit hole 3053. Once the tip of the needle 2010 of the needle apparatusextends through the exit hole 3053 the needle 2010 is grasped with aneedle-holder and pulled through until the thread 2020 provides a visualdetermination that the carrier is loaded properly and the seeds are intheir proper location. When the seed is placed at the proper depth allof the offset color 2030 (such as purple) thread disappears inside ofthe tile 601 and loader device and the regular color thread 2025 istrimmed away.

FIG. 15 is a top plan view of an embodied gore carrier 1201 similarlyshown in FIGS. 10A and 10B when placed in the loading bed 3070 of loaderdevice 3000 of FIG. 13. FIG. 15 shows the gore 1201 is placed within theloading bed 3070 portion of the loader 3000. The lid 3020 portion of theloader has been removed so that the gore 1201 is visible and one can seethat the orientation lines 1255 of the gore 1201 aligns directly to theloading channel support structure 3055 such that when a needle loaderenters through the proximal end loading channel 3051 and extends throughthe loading channel support structure 3055 and enters into the loadingbed portion 3070 of the base 3010 where a carrier gore 1201 is in asecured position the loading needle enters into the predeterminedplacement on the gore 1201 based on dosimetry needs for treatment. Thegore 1201 loaded the same as described for the tile 601 in FIG. 14. Oncethe gore 1201 is loaded, it may be trimmed along the trim lines 1259present on the antipodal surface 1210 of the gore 1201 if necessary.

Application and Treatment with Customized Radionuclide Carrier Systems

The specialized carriers of the present invention provide for certainprecise dimensions to allow the carriers to guide users (neurosurgeons,cardiothoracic surgeons, general surgeons, dermatologists, radiationoncologists, urological surgeons, veterinarians or other qualifiedproviders) in maintaining precise and preplanned dosimetry needed toproduce effective and safe outcomes.

The dosimetrically customizable implants of the present invention may beused as a means of treating, curing, ameliorating, or slowing theprogression of various tumors of the body, including but not limited to;tumors of the central nervous system, head and neck, spine, softtissues, bone, liver, lung, breast, skin, esophagus, stomach,intestines, colon, rectum, prostate, pancreas, retroperitoneal space,kidney, bladder, pelvis, ovary, cervix, fallopian tubes, uterus, andvagina.

The embodied carrier systems may be used in methods to facilitateintracavitary, intraluminal, interstitial, and external surfacebrachytherapy used with and without surgical resection of the tumors.

The embodied carrier systems may be used in methods specifically fortreating extracranial, interstitial, intra-cavitary, surface or visceralsite irradiation treatment of various primary and metastatic tumors.

The custom radionuclide carrier systems of the present invention may beused for implantation within the central nervous system and include aradiolabeled implant for interstitial implantation comprising asubstantially rigid implantable matrix design to be a carrier forradioactive seeds to produce a dosimetrically customizable implant inreal-time for each patient and lesion.

The dosimetrically customizable implants described herein may be used totreat, cure ameliorate or slow-down the progression and thus provide adefense against various brain tumors including but not limited to,meningioma, glioma, metastatic cancer and craniopharyngioma.

The rigid implantable matrix designs may include a design wherein thematrix is an implantable tile. The methods of above with the use oflow-energy radioactive seeds Cs 131, Ir 192, I125, Pd 103 or otherisotopes to be used intraoperative following surgical resection as apermanent implant.

The types of tumors to be treated include primary, secondary andrecurrent tumors involving the central nervous system.

A program/spreadsheet/nomogram to guide planning implants and orderingof seeds/tiles based on preoperative lesion size, shape, location,histology and number may be provided to assist the user when using thepresent carrier systems.

FIGS. 16-18 demonstrate some of the exemplary surgical applications andcustomization process that can be achieved with the tile carriers or thegore carriers or combinations of the two carriers.

FIG. 16 shows the pre-operation shape and locations of tumors in threecommon places and geometries. In position A the tumor is rounded inshape and located at or very near the brain surface. In position B thereare two tumors shown as rounded in shape but the tumors have differentaccessibilities in that the tumors may be deeper into the brain tissuefor B1 than B2. In position C there are two variable lesions C1 and C2where there is an irregular tumor bed shape and the lesion may be in anyvariety of shape and depth.

FIG. 17 shows the post-operation cavity shape location associated witheach of the above pre-op positions. The position A is considered concavein shape with a surface flair. The position B1 post-op is consideredconcave deep and stovepipe. The position B2 post-op is considered aBi-concave bed. The position C1 is now considered regular with anirregular bed. And position C2 is considered irregular, with anirregular bed and variations.

For each of these tumors/tumor beds there is a high variability of sizeshape and location but the options for the surgeon with the carriers ofthe present invention are almost unlimited in creating coveragepossibilities with the tiles or gores or a combination of the two.

FIG. 18 shows embodied carrier solutions for each of the above tumorbeds. The carrier solution for the position A tumor bed that isconsidered concave in shape with a surface flair would be for the userto use a petal and flap gore with an extended flap such as gore carrier1101 shown in FIG. 9B. The carrier solution for the position B1 post-opwhich is considered concave deep and stovepipe would be for the user touse a petal and flaps gore such as the gore carrier 1001 shown in FIG.9A. The carrier solution for the position B2 post-op which is considereda Bi-concave bed would be for the user to use a double petal gore suchas the gore carrier 1201 shown in FIG. 10. The carrier solution for theposition C1 which is considered regular with an irregular bed would befor the user to use one or more gores to fit and then additional tileconfigurations to fill as needed. The carrier solution for the positionC2 which is considered irregular, with an irregular bed and variationswould be for the user to use just the tile carriers because of the lackof space for a full gore implant.

This invention would also be useful in veterinary oncology, either aloneor in combination with surgery. Fractionated radiation therapy islogistically more difficult and costly in animals, which requireanesthesia prior to delivery of each fraction. Customizable BT,utilizing this invention, will enable delivery of effective andefficient treatment in properly selected tumors.

Although the invention has been described with reference to the aboveexample, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

What is claimed is:
 1. A treatment apparatus configured for placement ina cavity of a mammal to apply radioactive energy from radionuclide seedsto at least some mammalian tissue forming the cavity, the treatmentapparatus comprising: a plurality of three-dimensional collagen-basedtiles each having a first surface, an opposing second surface parallelto the first surface, and a uniform thickness of about four millimeterstherebetween; and a plurality of cylindrical radionuclide seeds, eachembedded in one of the tiles at an offset position between the first andsecond surfaces such that the radionuclide seeds are substantiallycloser to the first surfaces than to the second surfaces of the tiles,wherein the cylindrical radionuclide seeds are positioned withinrespective tiles such that a longitudinal axis of the cylindricalradionuclide seeds is substantially parallel to first surfaces ofrespective tiles in which the cylindrical radionuclide seeds areembedded; wherein one of the first surface or the second surface of eachof the tiles includes a textural feature usable by a user to distinguishbetween the first and second surfaces of the tiles such that each of thetiles may be inserted into the cavity at a desired orientation withreference to first and second surfaces.
 2. The treatment apparatus ofclaim 1, wherein the offset position is about three millimeters from thesecond surface and about one millimeter from the first surface.
 3. Thetreatment apparatus of claim 1, wherein the first and second surfacesare substantially circular.
 4. The treatment apparatus of claim 1,wherein the first and second surfaces are substantially rectangular. 5.The treatment apparatus of claim 1, wherein the tiles are configured forpermanent implantation into the cavity.
 6. The treatment apparatus ofclaim 1, wherein the textural feature of the tiles is usable by a userin placement of tiles with reference to other tiles already in thecavity.
 7. The treatment apparatus of claim 1, wherein the radioactiveseeds include radioisotopes emitting beta or alpha particles.